Plasma proinsulin, C-peptide and insulin in diagnostic suppression tests for insulinomas.
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Adenoma, Islet Cell↗
Biomedical subjects
L G Heding
Publications and source records attributed to L G Heding.
C-peptide in juvenile diabetics beyond the postinitial remission period. Relation to clinical manifestations at onset of diabetes, remission and diabetic control.
A group of 58 diabetics, age 6-17 years and with a duration of diabetes of 3-14 years was studied in order to show whether the nature of the clinical manifestations and the treatment at the onset of the disease are related to the subsequent C-peptide production and also whether remaining C-peptide production is related to better diabetic control. The relations between a number of clinical and laboratory variables were analysed including the degree of ketosis and the insulin dose given at onset of diabetes, the incidence of postinitial remission period, the fasting C-peptide level after the remission period, the level of insulin antibodies and the actual diabetic control expressed as the degree of glucosuria in the patients' urine tests at home. Multiple regression analysis was the main method used. Postinitial remission was positively correlated to initial insulin dose and negatively correlated to duration of ketonuria at onset. C-peptide, which was found in 24.1% of the patients was positively correlated to age at onset and initial insulin dose, but negatively correlated to ketonuria at onset. Diabetic control was positively correlated to insulin dose at onset and to C-peptide level, but negatively correlated to insulin antibodies. It could further be shown that patients who had received a more vigorous treatment immediately at onset had both a higher incidence of postinitial remission and a better diabetic control. The results suggest that an early diagnosis followed by rapid normalization of the metabolism at the onset of juvenile diabetes increase the possibility of preservation of some of the endogenous insulin production, which seems to facilitate diabetic control.
Adolescent↗
Human proinsulin in insulin-treated juvenile diabetics.
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Adolescent↗
C-peptide in juvenile diabetes.
C-peptide can be used as a measure of endogenous insulin secretion in insulin treated diabetics with insulin antibodies. At the onset of juvenile diabetes insulin production is thought to be absent or minimal, but we have found rather high levels of C-peptide, even in ketoacidotic patients. The ketoacidosis does not mean an irreversible beta cell failure. In the postinitial remission period with stable metabolism many patients have normal or almost normal C-peptide levels and their beta cells have the capacity to respond to natural stimulation with an increased insulin secretion. For some unknown reason the metabolism becomes more labile coinciding with decreasing C-peptide values. However, even several years beyond the postinitial remission period many juvenile diabetics have some persistent beta cell function, and it has been shown that even trace remnants of beta cell function are of importance for stabilization of the metabolism. There is no reason to believe that the beta cell failure should be predetermined e.g. by genetic factors. However, little is known how to influence the progression and stop the increasing beta cell failure. Some of our results suggest that an early detection and an intensive treatment of diabetes before severe metabolic disturbances and pronounced insulin deficiency have appeared, may increase the possibility of preserving some beta cell function.
Adolescent↗
C-peptide in diabetic children after stimulation with clucagon compared with fasting C-peptide levels in non-diabetic children.
Fasting serum C-peptide and total immunoreactive insulin (IRI) were determined in 38 non-diabetic children and adolescents 6-22 years old. C-peptide varied between 0.22-0.73 pmol/ml (mean +/- SD, 0.45 +/- 0.11). There was a tendency to higher values during puberty. No difference was found between subjects with or without a family history for diabetes. IRI varied between 0-31 millimcron/m1 (mean +/- SD, 11.3 +/- 6.5). The C-peptide response to glucagon was studied in 10 insulin dependent juvenile diabetics 11-19 years old, who had had measurable amounts of fasting C-peptide on some occasions during the previous years. Duration of diabetes varied between 4-12 years. A slight but significant rise in C-peptide level occurred in 3 patients. Their metabolic control estimated on the basis of daily urinalysis was "excellent" or "good". The results support the hypothesis that even trace remnants of the beta cell function may be of importance for the metabolic control in juvenile diabetes.
Adolescent↗
C-peptide in children with juvenile diabetes. A preliminary report.
Serum C-peptide, insulin-binding IgG and total insulin (IRI) were determined in 96 juvenile diabetics aged 4-21 years, with onset of diabetes at the age of 1-16 years and with 2-17 years' duration of diabetes. Thirty-four patients (35.4%) had detectable levels of C-peptide (greater than or equal to 0.04 pmol/ml). Compared to non-diabetic adults, 19 had values below the normal range, 12 showed values within the normal range (0.18-0.63 pmol/ml) and 3 rated above normal. There was a negative correlation between the fasting C-peptide concentration and the degree of ketonuria at the onset of diabetes and a positive correlation between C-peptide levels and the incidence of post-initial remission periods. Patients without detectable C-peptide had significantly higher levels of insulin antibodies than those who had detectable levels of C-peptide. The possibility of a relationship between the intensity of the initial treatment of diabetes and the preservation of the B-cell function is discussed, as well as the possibility of insulin antibodies being a cause of B-cell exhaustion.
Adolescent↗
Structure-function relationship: immunologic.
It is suggested that the antigenic site of glucagon for the specific sera is located within the 24-29 section of the molecule and within the 2-23 section for the fully cross-reacting sera. Biologically inactivated glucagon may retain immunoreactivity in spite of the loss of receptor-binding activity.
Animals↗
Separation of the two double-chain bovine intermediates of the proinsulin-insulin conversion I. Chemical, immunochemical, circular dichroism, and biological characterization.
The intermediates of the proinsulin-insulin conversion were separated by cation exchange. The circular dichroism spectra of the intermediates showed less alpha-helix than insulin and proinsulin. It is suggested that the C-peptide interacts with the section of alpha-helix contained between residues 2 and 8 in the A-chain of the insulin moieties and unwinds the alpha-helix. The in vivo activities of the intermediates were found to be in the order of 50% relative to insulin. In the fat cell assay, the A-chain-substituted form is weaker (9%) than the B-chain-substituted form (19%). The C-peptide segments of the two forms reacted with C-peptide-specific antibodies as fully as the free C-peptide, on a molar basis. In contrast, the insulin segments were hindered from reacting with insulin-specific antibodies as fully as the insulin.
Amino Acids↗
Effect of sugars, hydrogen ion concentration and ammonium nitrate on the formation of citric acid by Aspergillus niger.
Aspergillus niger Mulder strain when grown on a synthetic medium containing urea as the sole source of nitrogen at pH 5.2, formed a mixture of citric and gluconic acids. On growing the organism at pH 2.0 the gluconic acid content was reduced but citric acid yield remained low. Addition of NH4NO3 to the medium lowered the gluconic acid yields to undetectable levels with a simultaneous increase in the citric acid content. Of the sugars used for the production of citric acid, sucrose in an unautoclaved medium was found to be the best carbon source. Sucrose medium if autoclaved at pH 2.0, or a mixture of glucose and fructose instead of sucrose gave lower yields of citric acid. Under optimum conditions only citric acid was produced and the yield was 66-68 per litre after a growth period of about 10 days.
Aspergillus↗
Human C-peptide in normal and diabetic subjects.
Concentrations of human C-peptide, IRI (immunoreactive insulin) and glucose were determined during oral glucose tolerance test (1.75 g glucose/kg ideal body weight) in 14 normal persons (N), 9 maturity-onset diabetics (DI) and 10 insulin-requiring diabetics (DII) never treated with insulin and in 3 formerly insulin treated diabetics. The mean fasting levels of C-peptide and IRI in the first three groups were: N: 0.37 +/- 0.02 nM and 0.048 +/- 0.009 nM, DI: 0.86 +/- 0.17 nM and 0.11 +/- 0.029 nM, DH: 0.37 +/- 0.04 nM and 0.063 +/- 0.009 nM. One hour after oral glucose ingestion, the respective values increased to: N: 2.53 +/- 0.20 nM and 0.52 +/- 0.077 nM, DI: 2.49 +/- 0.31 nM and 0.49 +/- 0.11 nM, DH: 0.49 +/- 0.05 nM and 0.11 +/- 0.014 nM. Although secreted from the pancreas in equimolar concentrations, the molar ratio of C-peptide to insulin in peripheral blood was about 7 in the fasting state, falling to about 5 in the glucose stimulated condition. Maturity-onset diabetics had higher fasting levels of C-peptide than normal subjects, in agreement with the IRI levels. Three patients previously treated with insulin and having insulin antibodies showed C-peptide responses significantly below the normal range. In one of these patients, the test was repeated 9 months later when the insulin antibodies had disappeared, and the C-peptide response observed at that time was much higher. It is suggested that insulin antibodies cause an impaired IRI - and consequently C-peptide response - by constantly removing insulin from the granules in the B-cell. In normal humans the peripheral C-peptide responses to the oral glucose load showed less relative variation than do the insulin responses. Therefore, a radioimmunoassay for C-peptide in addition to the assay for insulin will provide supplementary information on insulinsecretion.
Antigens↗
The effect of phenformin upon the plasma pancreatic and gut glucagon-like immunoreactivity in diabetics.
Five patients with mild maturity-onset diabetes were given 250 ml of a 20% glucose solution by intraduodenal infusion and eight other patients similarly received an amino acid solution in a dose of 0.5 g amino acids per kg body weight. The pancreatic and gut glucagon-like immunoreactivity (pancreatic GLI and gut GLI) in plasma were measured before and after the application of the two stimuli. Each person was tested twice; the first (control) test was followed by a second test after three days of treatment with phenformin 150 mg daily, plus the same 150 mg dose taken 60 min before the intubation. The plasma pancreatic GLI increased slightly during both infusions, but was not affected by phenformin. Intraduodenal infusion of both glucose and the amino acid solution induced a greater rise in plasma gut GLI. After treatment with phenformin, the fasting plasma gut GLI was higher than the control value in eleven of thirteen patients. In most cases higher gut GLI plasma levels were also found after duodenal administration of glucose and amino acids. These data furnish further evidence of the local action of antidiabetic biguanides on the intestinal wall, including its hormonal activity. The hypothesis is advanced that the phenformin-induced increase in gut GLI secretion may bring about competition of the latter with pancreatic glucagon for receptors in liver cell membranes, reducing the effect of glucagon on the liver, and thus contributing to a decrease in glycaemia.
Adult↗
Serum IRI in insulin-treated diabetics during a 24-hour period.
Serum immunoreactive insulin extracted with acid ethanol (total IRI) and blood glucose were measured in two groups of diabetics and a control group during 24-hour periods. One group of diabetics had received insulin for less than 1 month, and none had yet developed insulin antibodies. The other had been treated with insulin for 2 years or more. The average level of total IRI in the diabetics without antibodies was similar to that in the normals, but highly elevated in diabetics with antibodies, although the blood glucose levels were similar in the two diabetic groups. The increase in total IRI after the insulin injections was more rapid in patients receiving quick-acting insulin and most pronounced in those with the highest levels of total IRI. The total IRI peaked in the afternoon and dropped during the night. The short-term insulin-treated patients showed a better degree of diabetes control than those treated for 2 years or more. No correlation was found however, between the total IRI level and the degree of control in the latter group. The patients with the highest levels of total IRI had the highest frequency of hypoglycemic episodes. This is in agreement with the concept that the insulin antibodies may function as a circulating depot, which releases insulin irrespective of the metabolic need.
Acetone↗
Radioimmunological determination of human C-peptide in serum.
A routing radioimmunoassay for human C-peptide in serum is described. Antibodies against human C-peptide were raised by immunizing guinea pigs with human b-component. Nine out of 12 animals produced useful antibodies within 6 months. Insulin antibodies coupled to Sepharose were used to bind human proinsulin and insulin in the serum and after centrifugation C-peptide was determined in the supernatant. The detection limit of the assay (calculated as 2 SD from zero) was about 0.003 pmole of C-peptide (in 100 mul). The main sources of error were: (1) Normal and diabetic sera devoid of C-peptide gave a displacement of 125I-Tyr-C-peptide varying from 0 to 0.16 nM (6 different antisera). Only one antiserum (M 1181) showed no displacement, and the values of C-peptide determined with this antiserum in normal and diabetic sera were lower than the values determined with another antiserum, which gave a value of 0.07 nM in the sera free of C-peptide. It is suggested that displacement found with most antisera is due to substances in serum that are not related to C-peptide or proinsulin. (2) Serial dilutions of pancreatic extracts and sera may yield dilution curves slightly different to those of the synthetic standard. Possible explanations are discussed. These sources of error can be eliminated or reduced by the proper selection of antisera. Fasting sera from 15 normals, 8 maturity-onset diabetics and 10 insulin-requiring diabetics showed the following concentrations of C-peptide: (M 1181) 0.35 +/- 0.09, 0.74 +/- 0.51 and 0.21 +/- 0.14 (nM, mean +/- SD). One hour after 1.75 g/kg oral glucose the values increased to 2.24 +/- 0.71, 2.34 +/- 0.24 nM.
Animals↗
Differential changes in the 5-hydroxytryptamine and insulin content of guinea-pig B-cells.
In the guinea-pig pancreas, 5-hydroxy-tryptamine (5-HT) occurs in the B-cells as well as in enterochromaffin cells scattered in the exocrine parenchyma. In the present study we examined the effects on the pancreatic 5-HT and insulin content of drugs known to affect the B-cells. For this purpose a radioimmunoassay of guinea-pig insulin was developed. Streptozotocin reduced the number of detectable B-cells and partially degranulated those that remained. It also lowered the insulin content of the pancreas and the 5-HT content of the B-cells but did not affect the 5-HT content of the enterochromaffin cells. Reserpine lowered the 5-HT content of both B-cells and enterochromaffin cells. The number and ultrastructure of the B-cells and the pancreatic insulin content was not affected. Streptozotocin + reserpine seemed to have additive effects of B-cell 5-HT. The results with these 2 drugs indicate that roughly 50% of pancreatic 5-HT is contained in the B-cells. Diazoxide markedly increased the pancreatic insulin content without affecting pancreatic 5-HT. Despite the fact that 5-HT and insulin are stored together in the cytoplasmic granules of the B-cells, 5-HT was differentially depleted from this store by reserpine. A marked disproportionality between 5-HT and insulin content was also induced by diazoxide.
Animals↗
Studies on polypeptides, VI. Synthesis, circular dichroism and immunological studies of tyrosyl C-peptide of human proinsulin.
The synthesis of tyrosyl human C-peptide, a sequence of 32 amino acids, by the fragment condensation of the N-terminal octapeptide and C-terminal tetracosapeptide is described. The t-butyl protecting groups were removed by trifluoroacetic acid to obtain N-benzyloxycarbonyl-tyrosyl C-peptide. The hydrogenolytic debenzyl-oxycarbonylation of this derivative proceeded to an extent of only 80-90%, and tyrosyl C-peptide was purified by preparative electrophoresis. This purified tyrosyl C-peptide led to an improved sensitivity of the radioimmunoassay. The synthetic tyrosyl C-peptide in an immunoassay using anti human b-component serum reacted slightly differently from the synthetic human C-peptide. After labelling tyrosyl C-peptide with 125I and then purifying the radioactive product, we observed that 80% of the radioactivity could be bound when reacted with an excess of the serum. The circular dichroism spectrum of tyrosyl C-peptide is very similar to that of synthetic human C-peptide. An analysis of the spectrum indicates that 3-7 amino acids are in the beta-structure and the rest in random coil conformation.
Amino Acid Sequence↗
Studies on polypeptides. V. Improved synthesis of human proinsulin C-peptide and its benzyloxycarbonyl derivative. Circular dichroism and immunological studies of human C-peptide.
An improved synthesis of human C-peptide is described. Five fragments: 33-39, 40-46, 47-49, 50-54 and 55-63 were used in the total synthesis. In the fully protected C-peptide the N-terminal alpha-amino function was blocked by a benzyloxycarbonyl group and the carboxyl and serine hydroxyl functions were blocked by t-butyl protection. The latter protecting groups were removed by trifluoroacetic acid to obtain N-alpha-benzyloxycarbonyl human C-peptide which, on catalytic hydrogenation, yielded human C-peptide. The immunoreactivity of the prepared human C-peptide was tested and found to deviate slightly from the human C-peptide synthesized earlier by another route. When tested in the immunoassay, human pancreatic extracts containing natural C-peptide (or fragments thereof) showed dilution patterns identical to that of the new synthetic C-peptide but different from that of the previously synthesized batch of C-peptide. The possible explantation for the observed differences in the immunoreactivity is discussed.
Benzyl Compounds↗
The influence of short term submaximal work on the plasma concentrations of catecholamines, pancreatic glucagon and growth hormone in man.
Studies were performed in 6 healthy, male volunteers to explore the effect of a work load on the blood concentrations of catecholamines in relation to pulse rate and blood pressure and the blood levels of pancreatic glucagon, insulin, growth hormone, glucose and glycerol. The work load consisted of 300 kpm/min for 5 min, followed by 600 kpm/min during the next 5 min and 900 kpm/min under a third 5 min period. The work load resulted in a marked increase in noradrenaline and adrenaline at 10 and 15 min of exercise. The pulse rate, the systolic pressure and the mean blood pressure were correlated to the blood levels of both adrenaline and noradrenaline. In spite of the rather marked activation of the sympathetic nervous system no increase occurred in glucagon as measured under exercise and up to 60 min after its completion. In 4 of the subjects the work load was followed by a prompt growth hormone response. The same 4 subjects also showed a marked increase in catecholamines. The 2 remaining subjects presented no change in growth hormone and their increase in catecholamines was relatively minor. Glycerol increased significantly during work and there was a positive correlation between the values recorded for glycerol and adrenaline. No significant changes occurred in blood sugar or insulin during work.
Adult↗
[Effect of phenformin on plasma levels of insulin, growth hormone, and pancreatic as well as intestinal glucagon in diabetics].
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Adult↗